1. Fate of drugs in the body1.1 absorption 1.2 distribution - volume of distribution

1.3 elimination - clearance

2. The half-life and its uses

3. The uses of the half-life

4. Plasma concentration-effect relationship

M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague, 2008

ABSORPTION

DISTRIBUTION

ELIMINATION Clearance

Volume of distribution

WHAT HAPPENS TO DRUGS INSIDE THE BODY

Administered

Absorbed

„Hidden“

Eliminated

Acting

protein binding

-plasma proteins

-tissue proteins

ONLY A FREE DRUG ACTS!The bound drug is inactive. Free and bound drug are in equilibrium. Displacement: drug-drug interactions

VOLUME OF DISTRIBUTION

Depends on:

Because the result of the calculation may be a volume greater than that of the body, it is an APPARENT (imaginary, not actual) volume

For example, Vd of digoxin is about 645 liters for a 70 kg man (i.e. about 9 times bigger than his actual volume)

VOLUME OF DISTRIBUTION

Vd = Amount of drug in body / Concentration of drug in plasma

Clinical importance of volume of distribution:

• When Vd of a drug is big it takes long time to achieve effective plasma concentration of the drug. In such cases a loading dose may be given to boost the amount of drug in the body to the required level. This is followed by administration of lower maintenance dose.

METABOLIC (biotransformation)

mostly in the liver

ENZYME INDUCTION/ INHIBITION

oxidase enzymes - cytochrom P450 (CYP2D6 etc)

GENETIC POLYMORPHISM

EXCRETIONkidneys metabolites or unchanged (almost completely

unchanged e.g. digoxin, gentamycin)

GIT... enterohepatic circulation e.g. tetracyclines

CLEARANCE

Clearance (CL) is the volume of plasma totally cleared of drug in unit of time (ml/min/kg)

CLtot total

CLR renal

CLH hepatic

CLNR nonrenal (= Cltot - CLR)

http://www.livestrong.com/article/288241-how-to-calculate-your-total-body-volume

Bathtube in a hotelwith two holes, no plugs,

and a plate with data Vd= 1000 L, CL = 100 mL/min

the half-life is the time taken for the plasma concentration to fall by half [plasmatic half-life]

Volume of distributiont ½ = 0,69 .Clearance

Linear kinetics (First order)

[t 1/2 is stable]

In most drugs after therapeutic doses:

plasma concentration falls exponentially

The rate of elimination is proportional to the concentration

In most drugs after therapeutic doses:

plasma concentration falls exponentially because elimination processes are not saturated

[some robustness to

dose increase]

Elimination is the bigger the higher is the level

Cmax

Cmin

Linear kinetics (First order)

The rate of elimination is proportional to the concentration

Elimination processes are saturated e.g. in alcohol, after higher doses of phenytoin, theophyllin

[unstable t 1/2 ]

Non-linear (Zero-order, saturation) kinetics

For example, in alcohol the rate of metabolism remains the same at about 1 g of alcohol for 10 kg of body weight per hour

The rate of elimination is constant

In a few drugs at therapeutic doses or in poisoning, elimination processes are saturated

elimination is constant, limited

Cmax

Cmin

Non-linear (Zero-order, saturation) kinetics

[low robustness to dose increase]

Kinetics

Half-life(plasmatic)

for anytherapeutic

dose

Robustnessto doseincrease

Predictability

Linear (First-order) stable good good

Non-linear(saturation,zero-order)

unstable poor poor

T1/2 as a guide to asses:

1/ At a single-dose: duration of drug action

2/ During multiple dosing:

•to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and

•when a steady state is attained (in 4-5 half-lifes)

3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

[t1/2 = 1 - 2 h]Ampicillin - single dose

T1/2 as a guide to asses:

1/ At a single-dose: duration of drug action

2/ During multiple dosing:

• to asses whether a drug is accumulated in the body (it is accumulated if the drug is given at intervals shorter than 1,4 half-lifes) and

• when a steady state is attained (in 4-5 half-lifes)

3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

THE USES OF THE HALF-LIFE

„PRINCIPLE OF 4-5 HALF-LIFES“:

If a drug is administered in intervals shorter than 1.4 half-life, then a steady state is attained after approximately 4-5 half-lifes

The time to attain the steady state is independent of dose.

Steady state

t1/2

Pla

sma

co

nce

ntr

ati

on

Interval Administered Initial plasmaconcentration atthe beginning of

intervalmicrog/ml

Remains atthe end of

intervalmicrog/ml

[Eliminatedduringinterval

microg/ml]

1. 100 mg 100 50 50

2. 100 mg 150 75 75

3. 100 mg 175 88 88

4. 100 mg 188 94 94

5. 100 mg 194 97 97

Attainment of steady state (SS) during multiple dosing of drug at intervals of 1 half-life

Why SS is attained after 4-5 half-lifes?

T1/2 as a guide to asses:

1/ At a single-dose: duration of drug action

2/ During multiple dosing:

•to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and

•when a steady state is attained (in 4-5 half-lifes)

3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

THE USES OF THE HALF-LIFE

Elimination of a drug during 5 half-lifes

of initial level % of total elimination

TIME TO STEADY STATE (attained after 4-5 half-lifes) independen of dose

FLUCTUATIONS• proportional to dose intervals• blunted by slow absorption

STEADY-STATE LEVELS (CONCENTRATIONS)proportional to dose

t1/2

REPEATED ADMINISTRATION OF DRUGS

Steady-state concentrations are proportional to dose

Linear kinetics - diazepamplasma concentrations

daily

daily

daily

Time (days)

toxic

therapeutic

Time (days)

therapeutic

toxic

plasma concentrationsNon-linear, saturation kinetics - phenytoin

daily

daily

daily

TIME TO STEADY STATE (attained after 4-5 half-lifes) independen of dose

FLUCTUATIONS• proportional to dose intervals• blunted by slow absorption

STEADY-STATE LEVELS (CONCENTRATIONS)proportional to dose

t1/2

REPEATED ADMINISTRATION OF DRUGS

How to reduce fluctuations in drug concentrations?

by administering drugs slowly, continually, e.g.:slow i.v. injection, infusion, sustained–release (SR) tablets, slow release from depots

(e.g. from patches transdermally, depot antipsychotics injected i.m.)

by administering a total dose (e.g. a daily dose) in parts at shorter intervals (mostly inconvenient)

or

Administration of parts of total dose at short intervals

• produces smaller fluctuations of drug concentrations (levels)

• an omission of a particular dose* does not need to cause an undesirable fall in drug concentrations (levels)

*noncompliance

Depends on:

• lipid solubility

• ionization (depends on pH) non-ionized (non-polar), local changes in the pH

• routes of administration

- per os

- presystemic elimination FIRST-PASS EFFECT

- pharmaceutical technologyBIOAVAILABILITY, bioequivalence

- parenteral

FIRST-PASS EFFECT:

loss of a drug by a metabolism mostly in the liver that occurs en route from the gut lumen to the systemic circulation

e.g. in nitroglycerin, morphine

Clinical consequence of the first-pass effect:

• limited effect after oral administration

• great interindividual differences in dosage

BIOAVAILABILITY:

the proportion of drug that reaches the systemic circulation

It is usually calculated from the AUC

(Area Under the Curve)